The present invention relates to a therapeutic method for treating or preventing a disease or condition of platelet aggregation in a subject wherein the method includes administering a pharmaceutically effective amount of a compound that inhibits platelet aggregation and specifically, thrombin induced platelet aggregation.
Heart disease, a common cause of death in today""s society, is often a result of ischemic syndromes that are produced by atherosclerosis and arteriosclerosis including myocardial infarction, chronic unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis and/or thrombosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and other cardiovascular devices. These syndromes represent a variety of stenotic and occlusive vascular disorders thought to be initiated by platelet aggregation on vessel walls or within the lumen by blood-born mediators thereby forming thrombin that restrict blood flow.
The basic mechanism of platelet aggregation has been well-studied. The mechanism starts with a blood vessel injury such as narrowing of the lumen, plaque formation, and the presence of foreign bodies/medical instruments. This injury leads to platelet activation and binding of fibrinogen and ligands. Upon ligand binding, the JAK (Janus-family Kinase) kinases, a family of cytoplasmic protein tyrosine kinases which mediate cytokine receptor signaling, undergo tyrosine phosphorylation and activate the cytoplasmic latent forms of the STAT family transcription factors (Signal Transducers and Activators of Transcription). In an investigation of platelet aggregation in mice deficient in JAK-3, which maps to human chromosome 19p12-13.1, a decrease in thrombin-induced platelet aggregation was discovered by the Applicant.
Gelotte, U.S. Pat. No. 5,972,967 and Scarborough, et al. U.S. Pat. No. 5,968,902 have described certain compounds and compositions that inhibit binding to a platelet by limiting the binding of fibrinogen. Nevertheless, there sill is a need for finding compounds and improved methods to treat or prevent a condition of platelet aggregation.
In accordance with the purpose(s) of this invention, as embodied and broadly described herein, this invention, in ore aspect, relates to a therapeutic method for treating or preventing a disease or condition of platelet aggregation in a subject including administering a pharmaceutically effective amount of a compound or composition that inhibits platelet aggregation and specifically, thrombin induced platelet aggregation.
In a second aspect, the invention relates to a method for treating or preventing a disease or condition of platelet aggregation in a subject by administering a pharmaceutically effective amount of a compound represented by formula (I): 
wherein:
X is selected from the group consisting of HN, R11N, S, O, CH2, and R11CH;
R11 is (C1-C4)alkyl or (C1-C4)alkanoyl;
R1-R5 are each independently selected from the group consisting of hydrogen, hydroxy, and halo where at least one of R1-R5 is hydroxy;
R6, R7, and R8 are each independently selected from the group consisting of hydrogen, hydroxy, mercapto, amino, nitro, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, and halo; and
R9 and R10 are each independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo, and (C1-C4)alkanoyl; or
R9 and R10 together are methylenedioxy; or a pharmaceutically acceptable salt thereof.
In another aspect, the invention relates to a method for treating or preventing a disease or condition of platelet aggregation in a subject by administering a pharmaceutically effective amount of a compound represented by formula (II): 
wherein:
R1-R5 are each independently selected from the group consisting of hydrogen, hydroxy, and halo where at least one of R1-R5 is hydroxy; and
a pharmaceutically acceptable salt thereof.
Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention as herein described. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several experimental examples and together with the description, serve to explain the principles of the invention